Kousuke Tani

Combined effects of prostaglandin E receptor subtype EP1 and subtype EP4 antagonists on intestinal tumorigenesis in adenomatous polyposis coli gene knockout mice

Previous studies have shown that prostaglandin E2 (PGE2) is involved in intestinal carcinogenesis through its binding to the PGE2 receptor subtypes EP1 and EP4 and activation of downstream pathways. ONO‐8711 and ONO‐AE2–227, prostaglandin E receptor subtype EP1‐ and EP4‐selective antagonists, respectively, are known to suppress formation of intestinal polyps in adenomatous polyposis coli gene‐deficient mice. The present study was designed to investigate the combined effects of EP1 and EP4 antagonists on spontaneous polyp formation in APC1309 mice in order to determine the contribution of each receptor to intestinal tumorigenesis. APC1309 mice were treated with 400 ppm of ONO‐8711 alone, 400 ppm of ONO‐AE2–227 alone or both in combination in the diet for 6 weeks. The mean area of polyps found in the intestine, calculated as the longer diameter × the shorter diameter ×π, was reduced by 12%, 43% (P<0.01) and 56% (P<0.01) of the mean control value (8.8 mm2) in the ONO‐8711 alone, ONO‐AE2–227 alone and combination treatment groups, respectively, suggesting clear additive effects of the combination. The same additive tendency for suppression was also observed with respect to the numbers of polyps in the intestine. Polyp size reduction was more remarkable with the EP4 antagonist, while the number reduction was more pronounced with the EP1 antagonist. Our results indicate that EP1 and EP4 may have separate intrinsic roles and, to some extent, contribute to polyp formation independently. Thus, combination treatment has potential for the chemoprevention of colon carcinogenesis.

Design and synthesis of a highly selective EP2-receptor agonist

EP2-receptor selective agonist 3 was identified by the structural hybridization of butaprost 1a and PGE(2) 2a. Based on this information, a chemically more stabilized 4 was discovered as another highly selective EP2-receptor agonist, iv administration of which to anesthetized rats suppressed uterine motility, while PGE(2) 2a stimulated uterine motility.

Palladiurn(0)-catalysed transfer hydrogenation of alkynes to cis-alkenes with HCO2H–NEt3

Transfer hydrogenation of alkynes using HCO2H–NEt3 as a hydrogen donor in the presence of Pd0-catalyst proceeds highly stereoselecively to afford cis-alkenes in excellent yields, thus providing a practical method for conversion of alkynes to cis-alkenes.

Development of a highly selective EP2-receptor agonist. Part 1: identification of 16-hydroxy-17,17-trimethylene PGE2 derivatives.

Design and synthesis of an EP2-receptor selective agonist began with the chemical modification of alpha- and omega-chains of butaprost 1a, which exhibits an affinity for the IP-receptor. Two series of prostaglandin (PG) analogues with a 16-hydroxy-17,17-trimethylene moiety as an omega-chain were identified. Among those tested, 4a,b,e,f,h and 6a,b,e,f,h were found to be highly selective EP2-receptor agonists. Structure-activity relationships are discussed.

Synthesis of optically active secondary allylic alcohols from allylsilanes via successive asymmetric dihydroxylation (AD) and Peterson olefination reactions

Abstract Optically active, secondary allylic alcohols can be prepared from allylic silanes by the sucessive asymmetric dihydroxylation and Peterson olefination reactions. The Effects of trialkylsilyl groups on the outcome of the AD reaction on vinyl and allyl silanes are also discussed.

Synthesis of optically active furfuryl alcohols and butenolides from trans-1-trimethylsilyl-3-alken-1-ynes via successive asymmetric dihydroxylation and hydromagnesiation reactions

Abstract Optically active furfuryl alcohols and hydroxy butenolides are prepared from trans-1-trimethylsilyl-3-alken-1-ynes by the successive asymmetric dihydroxylation and hydromagnesiation reactions.

A practical synthesis and biological evaluation of 9-halogenated PGF analogues.

A series of 9-halo PGF analogues 1-2 and 5-13 were synthesized and biologically evaluated. Among the compounds, 2 was the best EP2-receptor agonist. A practical method of synthesizing 2 via the Julia olefination of an aldehyde 3 with an optically active sulfone 4, which was prepared by Sharpless asymmetric epoxidation of 15, was developed. Other 9-halogenated PGF analogues were synthesized essentially by the same procedure and evaluated. The absolute configuration of 16-OH of 2 was determined as S by the X-ray analysis of a salt consisting of a 1/1 molar ratio of 2 and L-lysine.

A highly efficient approach to prostaglandins via radical addition of α side-chains to methylenecyclopentanones. Total synthesis of natural PGE1, limaprost and new prostaglandin derivatives.

Abstract Reaction of methylenecyclopentanones 2 with alkyl iodides via radical 1,4-addition pathway proceeds in good yields, thus providing an easy method for synthesis of not only known prostaglandins such as PGE 1 and Limafrost but also new prostaglandin derivatives.

Discovery of new orally active prostaglandin D2 receptor antagonists.

To identify an orally available drug candidate, a series of 3-benzoylaminophenylacetic acids were synthesized and evaluated as prostaglandin D(2) (PGD(2)) receptor antagonists. Some of the compounds tested were found to exhibit excellent inhibitory activity against cAMP accumulation in human platelet rich plasma (hPRP), which is one of the indexes of DP antagonism. The optimization process including improvement of the physicochemical properties such as solubility, which may result in an improved pharmacokinetic (PK) profile, is presented. Optimized compounds were studied for their pharmacokinetics and in vivo potential. A structure-activity relationship study is also presented. Some of the test compounds were found to have in vivo efficacy towards the inhibition of PGD(2)-induced and OVA-induced vascular permeability in guinea pig conjunctiva.

Synthesis and pharmacological activities of 13-Dehydro derivatives of primary prostaglandins

13-Dehydro derivatives of prostaglandin E1, E2, E3, F1 alpha and F2 alpha were synthesized. Compared with natural prostaglandins, 13-dehydro analogues were found to exhibit more potent inhibitory activity against human platelet aggregation and relaxation of guinea-pig isolated trachea, while they showed less potent activity of contraction of guinea-pig isolated ileum.